Targeting the IRAK1–S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma
Open Access
- 1 March 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (5), 1413-1425
- https://doi.org/10.1158/0008-5472.can-20-2125
Abstract
Novel strategies to treat late-stage nasopharyngeal carcinoma that often develop resistance to chemotherapy remains an unmet clinical demand. In this study, we identify the multi-kinase inhibitor pacritinib as capable of resensitizing the response to paclitaxel in an acquired resistance model. Transcriptome analysis of paclitaxel-sensitive and -resistant cell lines, as well as chemorefractory clinical samples, identified S100A9 as the top candidate gene suppressed by pacritinib and whose overexpression was significantly associated with paclitaxel resistance and poor clinical outcome. Moreover, both paclitaxel-resistant nasopharyngeal carcinoma cells and relapsed/metastatic clinical samples exhibited increased IRAK1 phosphorylation and demonstrated that pacritinib could abolish the IRAK1 phosphorylation to suppress S100A9 expression. Functional studies in both in vitro and in vivo models showed that genetic or pharmacologic blockade of IRAK1 overcame the resistance to paclitaxel, and combined treatment of pacritinib with paclitaxel exhibited superior antitumor effect. Together, these findings demonstrate an important role for the IRAK1–S100A9 axis in mediating resistance to paclitaxel. Furthermore, targeting of IRAK1 by pacritinib may provide a novel therapeutic strategy to overcome chemoresistance in nasopharyngeal carcinoma. Deregulation of the IRAK1–S100A9 axis correlates with poor prognosis, contributes to chemoresistance in nasopharyngeal carcinoma, and can be targeted by pacritinib to overcome chemoresistance in nasopharyngeal carcinoma.Keywords
Funding Information
- China Postdoctoral Science Foundation (2019M663295)
- National Natural Science Foundation of China (81972596)
- National Natural Science Foundation of China (81772963)
- National Natural Science Foundation of China (81425018)
- National Natural Science Foundation of China (81672868)
- Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638)
- Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S252)
- The Sci-Tech Project Foundation of Guangzhou city (201707020039)
- Bureau of Science and Information Technology of Guangzhou Municipality | Pearl River S and T Nova Program of Guangzhou (201806010135)
- the Natural Science Foundation of Guangdong Province for Distinguished Young Scholar (2018B030306001)
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